Hepatic senescence accompanies the development of NAFLD in non-aged mice independently of obesity

Senescence is considered to be a cardinal player in several chronic inflammatory and metabolic pathologies. The two dominant mechanisms of senescence include replicative senescence, predominantly depending on age-induced telomere shortening, and stress-induced senescence, triggered by external or intracellular harmful stimuli. Recent data indicate that hepatocyte senes-cence is involved in the development of nonalcoholic fatty liver disease (NAFLD). However, previ-ous studies have mainly focused on age-related senescence during NAFLD, in the presence or ab-sence of obesity, while information about whether the phenomenon is characterized by replicative or stress-induced senescence, especially in non-aged organisms, is scarce. Herein, we subjected young mice to two different diet-induced NAFLD models which differed in the presence of obesity. In both models, liver fat accumulation and increased hepatic mRNA expression of steatosis-related genes were accompanied by hepatic senescence, indicated by the increased expression of senes-cence-associated genes and the presence of a robust hybrid histo-/immunochemical senescence-spe-cific staining in the liver. Surprisingly, telomere length and global DNA methylation did not differ between the steatotic and the control livers, while malondialdehyde, a marker of oxidative stress, was upregulated in the mouse NAFLD livers. These findings suggest that senescence accompanies NAFLD emergence, even in non-aged organisms, and highlight the role of stress-induced senes-cence during steatosis development independently of obesity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.